Drug use disorder and risk of incident and fatal prostate cancer among Swedish men: a nationwide epidemiological study

Purpose Prostate cancer is the second most common cancer in men and a leading cause of cancer mortality worldwide. Men with drug use disorders (DUD) may potentially be at high risk for prostate cancer mortality because of delayed diagnosis and/or undertreatment. In this study, we aimed to investigate prostate cancer incidence, mortality, and stage at time of diagnosis among men with DUD compared to the general male population in Sweden. Methods We performed a follow-up study based on Swedish national register data for the period January 1997–December 2016. The study was based on 1,361,532 men aged 50–75 years at inclusion, of whom 9,259 were registered with DUD. Cox regression analysis was used to compute adjusted hazard ratios (HRs) for incident and fatal prostate cancer, and cancer stage at time of diagnosis, associated with DUD. Results DUD was associated with a slightly increased risk of incident prostate cancer (HR: 1.07, 95% confidence interval [CI] 1.00–1.14, p = 0.048) and substantially higher risk of fatal prostate cancer (HR: 1.59, 95% CI 1.40–1.82, p < 0.001), adjusted for age, socioeconomic factors, and comorbidities related to tobacco smoking and alcohol use disorder. No association was found between DUD and prostate cancer stage at diagnosis. Conclusions Men with DUD have an increased risk of fatal prostate cancer, possibly related to undertreatment in this patient population. Our findings should raise attention among medical staff and decision-makers towards a disadvantaged group of men in need of easily accessible prostate cancer evaluation and treatment.

Evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer in the multi-ancestry Million Veteran Program cohort

Importance: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man's risk of dying from prostate cancer and thus inform screening decisions, especially in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Objective: Determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Design: Million Veteran Program (MVP) cohort study, 2011-2021. Setting: Nation-wide study of United States military veterans. Participants: Population-based volunteer sample of male participants. Exposure(s): Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. Main Outcome(s) and Measure(s): Study designed after MVP data collected. Primary outcome: age at death from prostate cancer. Key secondary outcome: age at diagnosis of prostate cancer metastases. Hypothesis: A germline genetic score (PHS290) is associated with risk of fatal (or metastatic) prostate cancer. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group (p<1e-16). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio for death from prostate cancer was 4.41 [95% CI: 3.9-5.02]. Corresponding hazard ratios for European, African, Hispanic, and Asian subsets were 4.26 [3.66-4.9], 2.4 [1.77-3.23], 4.72 [2.68-8.87], and 10.46 [2.01-101.0]. When accounting for family history and ancestry group, PHS290 remained a strong independent predictor of fatal prostate cancer. PHS290 was also associated with metastasis. PHS290 was higher, on average, among men with African ancestry. Conclusions and Relevance: PHS290 stratified US veterans of diverse ancestry for lifetime risk of metastatic or fatal prostate cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

Prostate cancer risk stratification improved across multiple ancestries with new polygenic hazard score

Introduction: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. Methods: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry — the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. Results: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. Conclusion: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10−180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

Common genetic and clinical risk factors: Association with fatal prostate cancer in the Cohort of Swedish Men.

65 Background: Clinical variables (age, family history, and genetics) are commonly used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores, including PHS, are associated with all prostate cancer and are not specific for fatal cancers, PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to available clinical variables improves associations with prostate cancer death. Methods: Genotype and phenotype data were obtained from a nested case-control subset (n=3,279; 2,163 were diagnosed with prostate cancer, 278 died of prostate cancer) of the longitudinal, population-based Cohort of Swedish Men. PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes history, and body mass index) were independently tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models were constructed with clinical variables and PHS. Log-likelihood tests compared models. Results: Median age at last follow-up and at prostate cancer death were 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol intake (HR 1.74 [1.40-2.15]), and diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. A multivariable clinical model including PHS46 improved associations for fatal disease ( p<10−15). On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol intake (HR 1.45 [1.19-1.76]), and diabetes (HR 0.62 [0.42-0.90]) all remained associated with prostate cancer death. Similar results were found using the newer PHS166. Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common clinical risk factors, including family history. Adding PHS to clinical variables may improve individualized prostate cancer risk stratification strategies.

Coffee consumption and risk of prostate cancer: a systematic review and meta-analysis

ObjectivesTo conduct a systematic review with meta-analysis of cohort studies to evaluate the association of coffee consumption with the risk of prostate cancer.Data sourcesPubMed, Web of Science and Embase were searched for eligible studies up to September 2020.Study selectionCohort studies were included.Data extraction and synthesisTwo researchers independently reviewed the studies and extracted the data. Data synthesis was performed via systematic review and meta-analysis of eligible cohort studies. Meta-analysis was performed with the “metan” and “glst” commands in Stata 14.0.Main outcomes and measuresProstate cancer was the main outcome. It was classified as localised prostate cancer which included localised or non-aggressive cancers; advanced prostate cancer which included advanced or aggressive cancers; or fatal prostate cancer which included fatal/lethal cancers or prostate cancer-specific deaths.ResultsSixteen prospective cohort studies were finally included, with 57 732 cases of prostate cancer and 1 081 586 total cohort members. Higher coffee consumption was significantly associated with a lower risk of prostate cancer. Compared with the lowest category of coffee consumption, the pooled relative risk (RR) was 0.91 (95% CI 0.84 to 0.98), I2= 53.2%) for the highest category of coffee consumption. There was a significant linear trend for the association (p=0.006 for linear trend), with a pooled RR of 0.988 (95% CI 0.981 to 0.995) for each increment of one cup of coffee per day. For localised, advanced and fatal prostate cancer, the pooled RRs were 0.93 (95% CI 0.87 to 0.99), 0.88 (95% CI 0.71 to 1.09) and 0.84 (95% CI 0.66 to 1.08), respectively. No evidence of publication bias was indicated in this meta-analysis.ConclusionsThis study suggests that a higher intake of coffee may be associated with a lower risk of prostate cancer.

Recommended Definitions of Aggressive Prostate Cancer for Etiologic Epidemiologic Research

Background In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research. Methods Among prostate cancer cases diagnosed in 2007 in the National Cancer Institute’s Surveillance, Epidemiology, and End Results-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV). Results In our case population (n = 55 900), 3073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM staging and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of category T4 or N1 or M1 or Gleason score of 8 or greater prostate cancer, because this definition had one of the higher PPVs (0.23, 95% confidence interval = 0.22 to 0.24) and reasonable sensitivity (0.66, 95% confidence interval = 0.64 to 0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses. Conclusions We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced category (T4 or N1 or M1), high-grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology.

Common genetic and clinical risk factors: Association with fatal prostate cancer in the Cohort of Swedish Men

Background: Clinical variables--age, family history, genetics--are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death. Methods: Genotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n=3,279; 2,163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests. Results: Median age at last follow-up/prostate cancer death were 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95%CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol (HR 1.74 [1.40-2.15]), diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol (HR 1.45 [1.19-1.76]), diabetes (HR 0.62 [0.42-0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer (p<10-15). Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common risk factors, including family history. Impact: Adding PHS to clinical variables may improve prostate cancer risk stratification strategies.